OBJECTIVE: The primary objective of this project is to determine if supplementation with multiple vitamins/minerals reduces the incidence and mortality of esophageal, stomach or other cancers. Secondary objectives are to examine new hypotheses relating to the etiology and prevention of upper gastrointestinal cancers. BACKGROUND: The highest rates of esophageal cancer in the world occur in Linxian, China, where cumulative death rates for this cancer to age 75 exceed 20%. Widespread deficiencies of multiple nutrients are considered the most likely cause, but consumption of pickled vegetables and moldy foods and exposure to nitrosamines and polycyclic aromatic hydrocarbons may also play a role. METHODS: We have conducted two randomized, double-blind, placebo-controlled intervention studies to evaluate supplementation with multiple vitamins/minerals as a prevention strategy for esophageal, stomach and other cancers. The Dysplasia Trial evaluated 3,318 persons with cytologic evidence of dysplasia supplemented for 6 years, while the General Population Trial evaluated 29,584 persons supplemented for 5 1/4 years. Biologic specimens (blood, toenails, cytology and histology specimens) were collected periodically throughout the trials. Since the end of the intervention period, the participants in both trials have been followed as a cohort. PROGRESS: Both trials concluded in 1991, and results showed that the combination of beta-carotene/vitamin E/selenium significantly reduced total mortality, total cancer mortality, and stomach cancer incidence and mortality. Analysis of data from 10 years of post-intervention follow-up (through May 2001) is in progress. A number of cohort and case-cohort studies relating baseline questionnaire variables, serum analytes and tissue analytes to later development of cancer have recently been completed. Results have shown: (1) a strong association between low serum selenium levels and increased ESCC and gastric cardia cancer risk; (2) no relation between serum carotenoids and risk of upper GI cancers; (3) a strong association between low serum alpha-tocopherol levels and increased ESCC risk; (4) a strong association between low tissue zinc levels and increased ESCC risk; (5) increased risk for both cardia and non-cardia gastric cancer among subjects with positive serology for H pylori; (6) no relation between fumonisin exposure and ESCC risk; (7) an association between tooth loss and risk of upper GI cancers; and (8) associations between several genetic polymorphisms and risk of ESCC and/or gastric cardia cancer.